tbuckley/cabot-search huggingface dataset:
LGG-20. LANDSCAPE OF FGFR ALTERATIONS IN PEDIATRIC AND AYA GLIOMAS
Authors: Liana Nobre, Sameer Farouk Sait, Julie Bennet, Alexandra Gianyini Larsen, I-Chen Ho, Francesca Gianno, Andrew Lin, Ingo Mellinghoff, Alexandra Miller, Robert Siddaway, Matthias Karijannis, Uri Tabori, Tejus Bale, Cynthia Hawkins
Journal: Neuro-Oncology (2023)

Abstract FGFR alterations including single nucleotide variants (SNV) and rearrangements represent common oncogenic alterations found in pediatric low-grade gliomas. From a population-based cohort of over 1800 pediatric and AYA (adolescent and young adult) gliomas, FGFR mutations were found in 6% of pediatric low-grade gliomas (LGG) and 16 % of IDH-WT AYA gliomas. Given the frequency of FGFR driver alterations, we assembled a large cohort of 370 FGFR mutated glioma across all ages (6 months to 87 years) 53% of which were LGG. In the pediatric patients, most (87%) of FGFR altered gliomas were low-grade; while in AYA patients only 67%. Fusions were more frequent in pediatric LGG (60%), while SNVs were more common in AYA LGG (57%). The rearranged genes also differed; pediatric LGG: 26% FGFR1 ITD, 20% FGFR1 fusions, 15% FGFR2 fusions. AYA LGG had equal frequency of FGFR1 and FGFR2 fusions (30%). In adults, high grade gliomas were more common (73%), and frequently had additional oncogenic drivers. In general, additional oncogenic drivers were more common with increasing age and grade. In contrast to pediatric and AYA LGG, FGFR3-TACC3 fusions represented 40% of adult cases. Interestingly, this fusion was also found in 10% of FGFR LGGs overall. Although analysis of clinical outcomes are still ongoing, in our preliminary data 18 patients with FGFR altered low grade gliomas were treated with targeted agents; 3 stopped due to toxicity and were not evaluated for response. From patients on MAPKi 1/6 had a minor response and 3/6 stable disease; while 6/9 on FGFRi had partial or minor responses with additional 3 patients recently initiated on the drug. FGFR alterations are frequently encountered in AYA and pediatric population, molecular characterization is important in guiding prognosis and therapy. Although encouraging, further studies are needed to assess the benefit of FGFR inhibition in these patients.
LGG-11. COGNITIVE, ACADEMIC, AND QUALITY OF LIFE OUTCOMES IN SURVIVORS OF PEDIATRIC LOW-GRADE GLIOMA: CHALLENGING THE ‘BENIGN TUMOR’ PERCEPTION
Authors: Sumanth Nagabushan, Mashaal Hamayun, Joanna E Fardell, Mark Donoghoe, Elizabeth Bland, Ann Bye, Erica Jacobson, Neevika Manoharan, David S Ziegler, Jordana K McLoone, Alexandra M Johnson, Richard J Cohn
Journal: Neuro-Oncology (2023)

Abstract High survival rates in pediatric low-grade gliomas (pLGG) may overshadow potentially significant long-term toxicities and functional impact. Chemo-radiation sequelae are well documented, in contrast to those who undergo surgical resection or observation alone. We performed a retrospective cohort study from 2000-2015, assessing cognitive, academic, and quality of life (QoL) impact on 45 eligible pLGG survivors aged 0-16 years at diagnosis, at a median 7.4 years post-treatment. A multidisciplinary panel oversaw proxy questionnaires for young children (&amp;lt;7 years), proxy and self-reported for adolescents (8-15 years) and self-reported for young adults (&amp;gt;15 years). Data included demographics; tumor and treatment; early school (young child) progress; academic and occupation achievement (adolescents and young adults); health; and lifestyle issues. The incidence of abnormalities in the domains studied were compared to published population statistics. 16% of survivors underwent observation alone, and 84% surgery (58% complete resection). 57% of survivors experienced cognitive deficits. Young children (50%) and adolescents (42%) had low cognitive functioning scores, correlating with poor academic (p &amp;lt; 0.01) and standardised school educational tests’ performance. 42% of mainstream school attendees required learning support; 33% examination assistance; 50% completed secondary education and 22% a tertiary degree, but had attention (young child and adolescent), and memory (young adult) issues. 65.9% of survivors had at least one neurological concern, highest in adolescents (70%). Language deficits (42.9%), pain, fatigue, and hearing loss (28.6 %) in young children; and vision/sleep difficulties (35%); fatigue (30%) and mobility (25%) in adolescents were reported. Young adults suffered headaches (47.1%) and fatigue (29.4%). Young children (57%) suffered more emotional disturbance than adolescents (16%). Anxiety (23%) and depression (14%) reflected poor QoL on Emotion Thermometer scales in all survivors. These findings challenge the ‘benign’ label of pLGG and highlights the importance of close psychosocial surveillance in helping survivors achieve their best emotional and educational potential.
OUTC-02. CASE SERIES OF HYPERMUTATED PEDIATRIC CNS TUMORS
Authors: Rose Parisi, Emma Horowitz, Roshal Patel, Gavrielle Rood, Acacia Bowden, George Turco, David Korones, Jeffrey Andolina, Melanie Comito, Matthew Barth, Lauren Weintraub
Journal: Neuro-Oncology (2023)

Abstract In pediatric central nervous system (CNS) tumors, high tumor mutational burden (TMB) (≥3 mutations/megabase (mut/Mb)) has been correlated with lower overall survival and higher rates of progression as compared to low TMB tumors (&amp;lt;3 mut/Mb). This study is the first to examine a subset of pediatric CNS hypermutated tumors (≥10 mut/Mb) in comparison to high TMB tumors. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 years diagnosed with a primary CNS tumor (high TMB, N=34; low TMB, N=55) at four academic medical centers from 2008 to 2021. Hypermutated tumors (N=3) were exclusively high grade tumors; subtypes were ependymoma, medulloblastoma, and oligodendroglioma. Hypermutated tumors had an average TMB of 65 mut/Mb (range=11-132 mut/Mb). Most of the hypermutated tumors had TP53 mutations (N=2; 67%) as compared to 29% of high TMB patients (N=12). Sixty-seven percent of patients with hypermutated tumors experienced tumor progression (N=2) as compared to 44% (N=15) of patients with high TMB tumors. Average time to progression was 2.4 years in hypermutated tumors and 1.4 years in high TMB tumors. No patients with a hypermutated tumor experienced a death event, as compared to 41% (N=14) of patients with high TMB. Although we report a small subset of hypermutated pediatric CNS tumors, this multi-institution case series suggests that hypermutated tumors may be associated with higher rates of progression, slower time to progression, and lower mortality as compared to high TMB tumors. Future research with a larger population of hypermutated tumors is needed to better characterize outcomes to optimize treatment for this subset of patients.
IMMU-08. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: AN IRRDC REPORT
Authors: Anirban Das, Nicholas R Fernandez, Adrian Levine, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Liana Nobre, Trevor J Pugh, Derek S Tsang, Birgit Ertl-Wagner, Daniel A Morgenstern, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Although the initial response to immune-checkpoint inhibition (ICI) for patients with DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging, the role of immune-based salvage approaches for those progressing on anti-PD1 monotherapy is unknown. METHODS We performed an international registry study of patients managed using central molecular, genomic, radiological review and treatment recommendations between 2015-2021. Post-progression treatment included re-irradiation where feasible, and continuation of anti-PD1 with anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally. RESULTS Among 75 patients with RRD-HGG receiving PD-1 blockade, 20 are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p&amp;lt;0.001). The combination of ipilimumab/nivolumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months but high autoimmune toxicities (54%). The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months). Several biological insights were gained. Early radiological ‘flare’ in 33% of RRD-HGG on combined immunotherapy and radiation were associated with immunogenic radiation induced signatures. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra. CONCLUSION These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.
SURG-03. LAYER-BY-LAYER CORE-SHELL NANOPARTICLES FOR THE DELIVERY OF HDAC INHIBITORS TO THE CENTRAL NERVOUS SYSTEM
Authors: Michael H Marand, Emily Han, Seung Hyun Kim, Paula T Hammond, Joelle P Straehla
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline gliomas (DMGs) present unique challenges in pediatric cancer care. The location of DMGs often renders the tumor inoperable and radiation produces only a temporary effect. One promising approach in DMG treatment is histone deacetylase (HDAC) inhibitors. However, HDAC inhibitors are difficult to deliver to primary central nervous system (CNS) tumors because of low blood-brain barrier (BBB) permeability and poor accumulation in tumor tissues. The BBB permeability is particularly restricting for DMGs, which maintain a relatively intact BBB. To overcome these delivery challenges, we developed a new polymer-lipid core-shell nanoformulation for the delivery of HDAC inhibitors to the CNS that does not rely on polyethylene glycol (PEG) for colloidal stability. Removing PEG allows for surface charge manipulation to generate charged nanoparticles amenable to layer-by-layer assembly with alternately charged polyelectrolytes. This modular platform allows the addition of targeting moieties to enhance the delivery of HDAC inhibitor core-shell nanoparticles across the BBB and into DMG cells. HDAC inhibitors panobinostat and quisinostat were loaded into core-shell nanoparticles comprised of a poly(lactide-co-glycolide) (PLGA) core and a phospholipid shell. Nanoparticles were characterized using dynamic light scattering and transmission electron microscopy exhibiting favorable properties for in vivo delivery (panobinostat nanoparticle diameter 91.6 ± 1.0 nm, polydispersity index 0.115 ± 0.013). The release of HDAC inhibitors from layered and unlayered core-shell nanoparticles was investigated using high-performance liquid chromatography. The deacetylating activity of nanoencapsulated agents was confirmed in vitro in patient-derived DMG neurosphere models. CNS pharmacokinetic parameters are currently being investigated after intravenous delivery of drug-loaded nanoparticles in non-tumor-bearing mice, including cerebrospinal fluid and brain tissue concentrations of the encapsulated agents. Future studies will investigate brain biodistribution of core-shell HDAC inhibitor nanoparticles in orthotopic DMG tumor-bearing mice, comparing intravenous and local delivery strategies.
RARE-03. GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL GERM CELL TUMORS: A COMMON DELETION AT BAK1 ATTENUATES THE ENHANCER ACTIVITY AND CONFERS RISK FOR THE BRAIN TUMORS IN CHILDREN ADOLESCENTS AND YOUNG ADULTS
Authors: Keita Terashima, Kyuto Sonehara, Yui Kimura, Yoshiko Nakano, Tatsuya Ozawa, Meiko Takahashi, Kenji Suzuki, Takashi Fujii, Yuko Matsuhita, Arata Tomiyama, Toshihiro Kishikawa, Kenichi Yamamoto, Tatsuhiko Naito, Tomonori Suzuki, Shigeru Yamaguchi, Tomoru Miwa, Hikaru Sasaki, Masashi Kitagawa, Naoyuki Ohe, Junya Fukai, Hideki Ogiwara, Atsufumi Kawamura, Satoru Miyawaki, Fumihiko Matsuda, Nobutaka Kiyokawa, Koichi Ichimura, Ryo Nishikawa, Yukinori Okada
Journal: Neuro-Oncology (2023)

Abstract Intracranial germ cell tumors (IGCTs) are rare brain tumors that mainly occur in children, adolescents and young adults with a particularly high incidence in East Asian populations. The biological basis of these tumors is still largely unknown. We conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry by using Infinium Asian Screening Array and other molecular biology methods. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 x 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. Expression quantitative trait locus (eQTL) analysis using the GTEx dataset reveals that the risk allele of rs3831846 has a down-regulating effect on BAK1 expression in a wide range of tissues. Further in-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity. BAK1 is a pro-apoptotic member of the BCL-2 family, thus our results suggested that the risk allele may contribute to IGCTs predisposition through down-regulating BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 x 10-4, Spearman’s ρ = 0.48). Of the 57 loci, 11 exhibit significant association with IGCTs and these loci were implicated in a broad range of biological pathways, including KIT/KITLG signaling, apoptosis regulation, and telomerase activity. The risk allele frequency of rs3831846 is higher in east Asia than Europe (0.49 vs. 0.20), which may provide a partial explanation for the ethnic difference in incidence. Nevertheless, our results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.
RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Mohammad H Abu-Arja, Mary Claire McGlynn, Mohammed Saad Zaghloul, Ahmed Elhemaly, Kelsey Bertrand, Amar Gajjar, Rebecca Ronsley, Andrea M Cappellano, Natalia Dassi, Malgorzata Czogala, Richard Graham, Sofi Jares Baglivo, Girish Dhall, Sumanth Nagabushan, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI) using SPSS software. RESULTS We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up. CONCLUSIONS Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.
RARE-05. MOLECULAR HETEROGENEITY OF PEDIATRIC CHOROID PLEXUS CARCINOMAS
Authors: Margarita Zaytseva, Ludmila Papusha, Ludmila Yasko, Alexander Karachunskiy, Galina Novichkova, Alexander Druy
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND: Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li–Fraumenisyndrome, though only about a half of CPCs develop fromsyndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course. METHODS: This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted5.2 years (absolute range 2.8–12.6 years). RESULTS: All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. Inseven tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0±17.9% vs. 85.7±13.2%; p=0.009. Transcriptomically, the cohort split into two polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3±17.8% vs. 100%; p=0.012. CONCLUSION: CPCs split into at least two molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates withsurvival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.
DIPG-52. EXTRAPONTINE PROGRESSION WITH STABLE PONTINE DISEASE POST-RADIOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ON A CONNECT TRIAL: IMPLICATIONS FOR RADIATION TREATMENT VOLUMES
Authors: Margot Lazow, Joshua Palmer, Joseph Stanek, Patricia Baxter, Diana Thomas, Ralph Salloum, Peter de Blank, Leonie Mikael, Shiva Senthil Kumar, Jeffrey Leonard, Elaine Mardis, Rachid Drissi, Maryam Fouladi, Diana Rodriguez
Journal: Neuro-Oncology (2023)

Abstract Radiotherapy remains the only treatment modality proven to prolong survival and alleviate symptom burden for patients with DIPG. Upfront focal photon radiation to 54 Gy with 1-1.5cm margins is standard. Subventricular, leptomeningeal, and/or spinal dissemination is observed in up to 50% of cases at autopsy, with activation of metastasis-related pathways (eg, epithelial-mesenchymal transition) in a subset of tumors. Given potential for metastatic spread and critical implications for radiation field volumes, we analyzed the frequency of extrapontine disease progression with pontine tumor stability within a prospective cohort with standardized longitudinal imaging. In a CONNECT consortium-sponsored phase Ib trial with a radiosensitizing agent administered concurrently with focal radiation and adjuvantly, among 10 patients with DIPG who experienced progressive disease with available serial imaging, four (40%) had evidence of disease extension and/or non-contiguous dissemination with stable pontine tumor size at a median of 9 months (range: 5-15 months) from diagnosis. Specifically, extrapontine progression was observed in the spinal cord (n=3), cerebellum (n=2), basal ganglia (n=1), temporal lobe (n=1) and/or leptomeninges and ependymal surfaces (n=1), without radiographic pontine disease progression. Five of the remaining six patients (who came off treatment due to pontine progression) subsequently had radiographic evidence of extrapontine extension (cerebellar, spinal, thalamic, supratentorial). Comprehensive molecular profiling is underway on biopsy or autopsy specimens for three patients, focusing on metastasis pathways. In summary, within a small prospective cohort with longitudinal imaging, we observed extrapontine progression despite local pontine disease control following focal radiotherapy in 40% of patients with DIPG at a median of 9 months after diagnosis. Further research will be essential to identify biological predictors of dissemination and corroborate findings in a larger cohort, but results suggest at least a subset of patients with DIPG may benefit from larger radiation volume expansion into contiguous structures and white matter tracts.